Process to produce oxazolidinones

ABSTRACT

The present invention includes a number of novel intermediates such as the (S)-secondary alcohol of formula (VIIIA)  
     X 2 —CH 2 —C*H(OH)—CH 2 —NH—CO—R N   (VIIIA)  
     and processes for production of pharmacologically useful oxazolidinones.

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims thebenefit of U.S. provisional application Serial No. 60/064,738 filed Nov.7, 1997, under 35 USC §119(e)(i). BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention is a process to prepare pharmacologicallyactive oxazolidinones and various intermediates used in the process.

[0003] 2. Description of the Related Art

[0004] Various 5-acetamidomethyloxazolidinones are well known to thoseskilled in the art as pharmacologically useful antibactericals. Variousmethods are well known to those skilled in the art for preparing theseuseful therapeutic agents.

[0005] U.S. Pat. Nos. 5,164,510, 5,182,403 and 5,225,565 disclose5′-indolinyloxazolidinones, 3-5′-indazolyl)oxazolidinones, 3-(fused-ringsubstituted)phenyloxazolidinones respectively useful as antibacterialagents.

[0006] U.S. Pat. Nos. 5,231,188 and 5,247,090 disclose various tricyclic[6.5.5] and [6.6.5]-fused ring oxazolidinones useful as antibacterialagents.

[0007] International Publication WO93/09103 discloses mono- and di-halophenyl oxazolidinone anti-bacterials which are useful as pharmaceuticalagents for their anti-bacterial action.

[0008] Prior art processes to make oxazolidinones involve condensationof an aromatic carbamate with a non-nitrogen caontaining three-carbonreagent to give an intermediate oxazolidinone with a hydroxymethylsubstituent at the 5-position. The hydroxyl must then be replaced by anacetamido group to give the pharmacologically active5-acetamidomethyloxazolidinones. Many variants of this essentiallytwo-step process have been developed.

[0009] U.S. Pat. No. 4,150,029, 4,250,318, 4,476,136, 4,340,606 and4,461,773 disclose the synthesis of 5-hydroxymethyloxazolidinones fromamines (R—NHX₁, where X₁ is —H or p-toluenesulfonyl) and R,S-glycidol(C^(#H)2—O—C^(#H—CH) ₂—OH where the carbon atoms marked^(#) are bondedtogether, cyclized to form an epoxide). The mixture of enantiomersproduced by this process (represented by the formulaR—NH—CH₂—CHOH—CH₂—OH) are separated by fractional crystallization of themandelic acid salts. The enantiomerically pure R-diol is then convertedinto the corresponding 5R-hydroxymethyl substituted oxazolidinones bycondensation with diethylcarbonate in the presence of sodium methoxide.These 5R-hydroxymethyl substituted oxazolidinones must be aminated in asubsequent step.

[0010]J. Med. Chem., 32, 1673 (1989), Tetrahedron 45, 1323 (1989) andU.S. Pat. No. 4,948,801 disclose a method of producing oxazolidinoneswhich comprises reacting an isocyanate (R—N═C═O) with (R)-glycidylbutyrate in the presence of a catalytic amount of lithiumbromide—tributylphosphine oxide complex to produce the corresponding5R-butyryloxymnethyl substituted oxazolidinone. The process is performedat 135-145°. The butyrate ester is then hydrolyzed in a subsequent stepto give the corresponding 5R-hydroxymethyl substituted oxazolidinone.The 5R-hydroxymethyl substituted oxazolidinone must then be aminated ina subsequent step.

[0011]Abstracts of Papers, 206th National Meeting of the AmericanChemical Society, Chicago, Ill., August, 1993; American ChemicalSociety. Washington, D.C., 1993; ORGN 089; J. Med. Chem. 39, 673 (1996);J. Med. Chem. 39, 680 (1996); International Publications WO93/09103,WO93/09103, WO95/07271 and WO93/23384; PCT applications PCT/US95112751and PCT/US95/10992; Abstracts of Papers, 35th Interscience Conference onAntimicrobial Agents and Chemotherapy, San Francisco, Calif., September,1995; American Society for Microbiology. Washington, D.C., 1995;Abstract No. F208; Abstracts of Papers, 35th Interscience Conference onAntimicrobial Agents and Chemotherapy, San Francisco, Calif., September,1995; American Society for Microbiology: Washington, D.C., 1995;Abstract No. F207; Abstracts of Papers, 35th Interscience Conference onAntimicrobial Agents and Chemotherapy, San Francisco, Calif., September,1995; American Society for Microbiology: Washington, D.C., 1995;Abstract No. E206; Abstracts of Papers, 35th Interscience Conference onAntimicrobial Agents and Chemotherapy, San Francisco, Calif., September,1995; American Society for Microbiology: Washington, D.C., 1995;Abstract No. F227;

[0012] disclose the reaction of a carbamate with n-butyllithium, lithiumdiisopropylamide or lithium hexamethyldisilazide at −78° to −40°followed by glycidyl butyrate at −78° followed by warming to 20-25° toproduce 5R-hydroxymethyl substituted oxazolidinones where the ester iscleaved during the reaction. The 5R-hydroxymethyl substitutedoxazolidinones must then be aminated in a subsequent step.

[0013] International Publication WO95/07271 discloses the ammonolysis of5R-methylsulfonyloxymethyl substituted oxazolidinones.

[0014] U.S. Pat. No. 4,476,136 discloses a method of transforming5-hydroxymethyl substituted oxazolidinones to the corresponding5(S)-aminomethyl substituted oxazolidinones (VII) that involvestreatment with methane sulfonyl chloride followed by potassiumphthalimide followed by hydrazine.

[0015]J. Med. Chem., 32, 1673 (1989) and Tetrahedron 45, 1323 (1989)disclose a method for transforming 5-hydroxymethylsubstitutedoxazolidinones into the corresponding 5S-acetamidomethyl substitutedoxazolidinones that involves treatment with methanesulfonyl chloride ortosyl chloride, followed by sodium azide, followed by trimethylphosphiteor platinum dioxide/hydrogen, followed by acetic anhydride or acetylchloride to give the desired 5(S)-acetamidomethyl substitutedoxazolidinone.

[0016] U.S. provisional application Serial No. 60/015,499 discloses aprocess to prepare 5(S)-hydroxymethyl substitued oxazolidinoneintermediates which are useful in the preparation of thepharmacologically active 5(S)-acetamidomethyloxazolidinoes. It futherdiscloses a process to convert the 5-hydroxymethyl substituedoxazolidinone intermediates into 5-aminomethyl substitued oxazolidinoneintermediates which can be acylated to produce the pharmacologicallyactive 5(S)-acetamidomethyl substitued oxazolidinones.

[0017]J. Med. Chem., 33, 2569 (1990) discloses the condensation of anisocyanate with racemic glycidyl azide to produce a racemic5-azidomethyl-substituted oxazolidinone. Two subsequent steps arerequired to convert the racemic azidomethyl-substituted oxazolidinoneinto racemic 5-acetamidomethyl-substituted oxazolidinone, which hasantibiotic activity. The present invention converts isocyanates into the(S)-enantiomer of acetamidomethyl-substituted oxazolidinones which havegreater antibiotic activity than the racemates, in one step.

[0018] U.S. Pat. No. 5,332,754 discloses (col. 2, lines 14-34) thatracemic oxazolidinone-CH₂—NH—Ac can be synthesized in one step bycondensation of a carbamate with racemic glycidyl acetamide “in thepresence of a base” such as an amine, “alkali metal hydroxide, an alkalimetal alkoxide, and the like”, and that “it is preferred to carry outthe reaction under heating . . . preferably at a temperature between 90°C. and 110° C.” (col. 4, lines 44-56). Evidence indicates that underthese conditions rearrangement to an undesired product occurs. Thepatent provides no yields or description of this process in theExamples. Indeed, the EXAMPLEs disclose not a one-step process butmulti-step routes that are known to those skilled in the art involvingmesylation of a 5-hydroxymethyl substituted oxazolidinone followed byazide displacement, hydrogenation and acetylation of the amine. Inparticular, see EXAMPLEs 59-63. The present invention differs in thatthe contacting between the carbamate (IX) and the epoxide (VIIIB) isperformed under conditions that competing rearrangement to the undesiredside products is largely suppressed.

[0019]Tetrahedron Letters, 37, 7937-40 (1996) discloses a sequence forsynthesis of S-glycidylacetamide (R²=—NHAc) and a process forcondensation of a carbamate with 1.1 equivalents of n-butyl lithium(THF, −78°) followed by 2 equivalents of S-glycidylacetamide to give thecorresponding 5S-acetamidomethyl-substituted oxazolidinone. The presentinvention differs in that the contacting between the carbamate (IX) andS-glydidylacetamide is performed in the presence of lithium alkoxidebases or the carbamate (IX) is contacted with the S-chlorohydrinacetamide (VIIIA) or S-chloroacetate acetamide (VIIIC) or an isocyanate(XIV) is contacted with the S-chlorohydrin acetamide (VIIIA).

[0020] U.S. Pat. No. 3,654,298 discloses the synthesis of5-alkoxymethyl-3-aryl-substituted oxazolidinones by sodium ethoxideinduced cyclization of chlorocarbamates. The present invention differsin that the substituent at the 5-position is acylamino.

SUMMARY OF INVENTION

[0021] Disclosed is an (S)-secondary alcohol of formula (VIIIA), an(S)-epoxide of formula (VIIIB), an (S)-ester of formula (VIIIC), an(S)-protected alcohol of the formula (IVA), an (S)-phthalimide alcoholof formula (IVC), an (S)-phthalimide epoxide of formula (IVD), an(S)-imine of glydidylamine of formula (IVB), an (S)-intermediate offormula (XV) and an (S)-oxazolidinone phthalamide intermediate offormula (XVI).

[0022] Also disclosed is a process for the preparation of a (S)-3-carbonamino alcohol of the formula (V) which comprises (1) contacting anon-nitrogen adduct of formula (I) with aqueous ammonia (II) in thepresence of an (S)-protected-epoxide of formula (III) and (2) contactingthe reaction mixture of step (1) with acid.

[0023] Further disclosed is a process for the preparation of an(S)-3-carbon amino alcohol of the formula (V) which comprises (1)contacting a phthalimide of formula (VI) with an (S)-protected-epoxideof formula (III) in the presence of potassium phthalamide in DMF or DMACto give an (S)-phthalimide alcohol of formula (IVC) and (2) contactingthe product of step (1) with aqueous acid.

[0024] Additionally disclosed is a process for the preparation of asecondary alcohol of the formula (VIIIA) which comprises (1) contactingan (S)-3-carbon amino alcohol of the formula (V) with an acylating agentand a tri(alkyl)amine.

[0025] Disclosed is a process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) of formula (X) which comprises (1)contacting a carbamate of formula (IX) with an oxygenated amino reagentselected from the group consisting of an (S)-secondary alcohol of theformula (VIIIA), an (S)-epoxide of the formula (VIIIB) or an (S)-esterof the formula (VIIIC) in the presence of a lithium cation and a basewhose conjugate acid has a pK_(a) of greater than about 8.

[0026] Also disclosed is a process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) of formula (X) which comprises (1)contacting a carbamate of formula (IX) with a phthalimide alcohol of theformula (IVC) or a phthalimide epoxide of the formula (IVD), in thepresence of a lithium cation and a base whose conjugate acid has apK_(a) of greater than about 8, (2) contacting the product of step (1)with aqueous acid, (3) contacting the reaction mixture of step (2) withan acid anhydride of the formula O(CO—R_(N))₂ or an acid halide of theformula R_(N)—CO—X₄ and a tri(alkyl)amine where alkyl is C₁-C₅.

[0027] Further disclosed is a process for the production of an(S)—R_(oxa)—RING-CH₂—NH—CO—R_(N) of the formula (X) which comprises (1)contacting a carbamate of the formula (IX) with a compound selected fromthe group consisting of a (S)-protected alcohol of the formula (IVA) ora (S)-3-carbon protected epoxide of the formula (IVB) in the presence ofa lithium cation and a base whose conjugate acid has a pK_(a) of greaterthan about 8 to produce a (S)-protected oxazolidinone of the formula(XII), (2) contacting the reaction mixture of step (1) with aqueous acidto produce an (S)-oxazolidinone free amine of the formula (XIII) and (3)contacting the product of step (2) with an acylating agent selected fromthe group consisting of an acid anhydride of the formula O(CO—R_(N))₂ oran acid halide of the formula R_(N)—CO—X₄ and where R_(N) is as definedabove and a tri(alkyl)amine where alkyl is C₁-C₅ where R_(oxa) is asdefined above.

[0028] Additionally disclosed is a process for the production of an(S)—R_(oxa)—RING-CH₂—NH—CO—RN of the formula (X) which comprises (1)contacting a carbamate of the formula (IX) in the presence of a lithiumcation and a base whose conjugate acid has a pK_(a) of greater thanabout 8 to produce an (S)-oxazolidinone free amine of the formula(XIII), and (2) acylating the (S)oxazolidinone free amine (XIII) with anacylating agent selected from the group consisting of an acid anhydrideof the formula O(CO—R_(N))₂ or an acid halide of the formula R_(N)—CO—X₄and a tri(alkyl)amine where alkyl is C₁-C₅.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention includes both novel intermediates andprocesses useful in the production of commercially valuableoxazolidinone antibiotics (X One of the novel processes is set forth inCHART D and is the reaction of a carbamate (IX) with either a(S)-secondary alcohol (VIIIA) or (S)-epoxide (VIIIB) or (S)-ester(VIIIC) to produce the corresponding pharmacologically active(S)-oxazolidinone-CH₂—CO—R₁ (X). A second process to produce thepharmacologically active (S)-oxazolidinone-CH₂—CO—R₁ (X) is set forth inCHART H and involves reaction of an isocynate (XIV) with a (S)-secondaryalcohol (VIIIA) to give the (S)-intermediate (XV) which is then readilytransformed to the corresponding pharmacologically active(S)oxazolidinone-CH₂—CO—R₁ (X).

[0030] The three carbon nitrogen containing fragments (S)-secondaryalcohol (VIIIA), (S)-epoxide (VIIIB) and (S)-ester (VIIIC) can beproduced in two differet ways. This fragment produces the two adjacentcarbon atoms of the oxazolidinone ring, the methylene carbon atomattached thereto as well as the nitrogen atom attached to the methylenegroup. These three carbon nitrogen containing fragments (S)-secondaryalcohol (VIIIA), (S)-epoxide (VIIIB) and (S)-ester (VIIIC) are producedaccording to the processes of CHART C.

[0031] CHART A discloses a process to prepare the (S)-3-carbon aminoalcohol (V) from the (S)—X₂-epoxide (III) using a non-nitrogencontaining adduct (I) and ammonia (II) as the source of nitrogen. In the(S)—X₂-epoxide (III), and other compounds of this invention # indicatesthat the atoms marked with a (^(#)) are bonded to each other resultingin the formation of a ring (epoxide). For the (S)—X₂-epoxides (III) itis preferred that X₂ be —Cl. The (S)—X₂-epoxides (III) are either knownto those skilled in the art or can readily be prepared from compoundsknown to those skilled in the art by methods known to those skilled inthe art For the non-nitrogen containing adduct (I) it is preferred thatX₀ is -φ; it is more preferred that X₀ is φ. The reaction of thenon-nitrogen adduct (I), ammonia (II) and the (S)—X₂-epoxide (III) isperformed as set forth in EXAMPLEs 1 and 14. It should be noted that ifone starts with enantiomerically pure (S)—X₂-epoxide (III) that one thenobtains enantiomerically pure (S)-protected alcohol (IVA). The absoluteconfiguration of the carbon atom in the pharmacologically useful(S)-oxazolidinone-CH₂—CO—R₁ (X) product is “S” and therefore it ispreferable to begin with enantiomerically pure (S)—X₂-epoxide (III) andobtain enantiomerically pure (S)— protected alcohol (IVA), see CHART AIn the CHARTS and CLAIMS the suprascripted “*” as —C* (a)(b)-denotes theasymetric carbon atom has the appropriate enantiomeric configuration(S)— such that when this carbon atom becomes part of the(S)-oxazolidinone-CH₂-CO—R₁ (X), it is the correct enantiomer. If onebegins any of the chemical sequences of the processes of the presentinvention with an optically impure (racemic) form rather than anenantiomerically pure form, it is apparent to one skilled in the artthat the products obtained will be the corresponding optically impure(racemic) forms.

[0032] The (S)-protected alcohol (IVA) is then contacted with an acid toform the corresponding (S)-3-carbon amino alcohol (V). Neither thenature, strength nor amount of the acid is critical. It is preferredthat the acid have a pK_(a) less than 4. It is immaterial whether theacid is organic or inorganic. The (S)-3-carbon amino alcohol becomes thecation and the nonproton portion of the acid is the anion. For exampleif the mixture is acified with sulfuric acid the (S)-3-carbon aminoalcohol (V) is obtained as the sulfate salt. The nature of the anion isnot important.

[0033] CHART B discloses a way to prepare the desired (S)-3-carbon aminoalcohol (V) from the same (S)—X₂-epoxide (III) but using a nitrogencontaining adduct (VI). In this situation, no ammonia (II) is needed. Inthe final step of the process, where the product of step one iscontacted with aqueous acid, it is preferred that the acid behydrochloric, hydrobromic, hydroiodic, sulfuric or p-toluenesulfonicacid.

[0034] CHART C discloses the process to convert the (S)-3-carbon aminoalcohol (V) to the corresponding (S)-secondary alcohol (VIIIA),(S)-epoxide (VIIIB) or (S)-ester (VIIIC) and the conversion of the(S)-secondary alcohol (VIIIA) to the corresponding (S)-epoxide (VIIIB)and (S)-ester (VIIIC) respectively. To convert the (S)-3-carbon aminoalcohol (V) to the corresponding (S)-secondary alcohol (VIIIA) the3-carbon amino alcohol (5) is reacted with an appropriate acylatingreagent such as an acyl halide or acyl anhydride under acylationreaction conditions well known to those skilled in the art, see EXAMPLE2. It is preferred that the acylating reagent be selected from the groupconsisting of an acid anhydride of the formula O(CO—R_(N))₂ where R_(N)is C₁-C₅ alkyl or an acid halide of the formula R_(N)—CO—X₄ where X₄ is—Cl or —Br and a tri(alkyl)amine where alkyl is C₁-C₅. It is morepreferred that R_(N) is C₁ alkyl and X₄ is —Cl. It is more preferredthat the acylating reagent be the acyl anhydride and it is preferredthat the acyl anhydride be acetic anhydride.

[0035] Alternatively, the (S)-epoxide (VIIIB) can be obtained byreaction of the (S)-ester (VIIIC) with bases such as sodium methoxide orpotassium carbonate/methanol. Also the (S)-3-carbon amino alcohol (V)can be transformed to the corresponding (S)-ester (VIIIC) by reactionwith acetic anhydride in pyridine, see EXAMPLE 3. The (S)-epoxide(VIIIB) can be produced from the corresponding (S)-secondary alcohol(VIIIA) by reaction with potassium t-butoxide in TBF at −20°, seeEXAMPLE 11. Further the (S)-secondary alcohol (VIIIA) can be transformedto the corresponding (S)-ester (VIIIC) by reaction with the acylatingreagents discussed above. For the (S)-ester (VIIIC), it is preferredthat R_(N) is —CO—CH₃.

[0036] CHART D discloses the process of reacting a carbamate of theformula R_(oxa)—NH—CO—O—CH₂—X₁ (IX) with either the (S)-secondaryalcohol (VIIIA), the (S) epoxide (VIIIB) or (S)-ester (VIIIC) to producethe corresponding (S)-oxazolidinone-CH₂—CO—R₁ (X). The carbamates (IX)are known to those skilled in the art or can be readily prepared fromknown compounds by methods known to those skilled in the art. It ispreferrred that X₁ is —H. R_(oxa) is phenyl substituted with one —F andone substituted amino group. Substituted amino groups include4-(benzyloxycarbonyl)-1-piperazinyl, 4-morpholinyl and4-hydroxyacetylpiperazinyl. It is preferred that R_(oxa) is3-fluoro-4-[4-(benzyloxycarbonyl)-1-piperazinyl]phenyl or3-fluoro-4-[4-morpholinyl)phenyl. The carbamate (IX) and the threecarbon unit (VIIIA, VIIIb or VIIIC) is reacted by contacting thereactants with a base. The nature of which is not critical so long as itis strong enough to deprotonate the carbamate (IX). Operable bases arethose whose conjugate acid has a pK_(a) of greater than about 8.Preferred bases include compounds selected from the group consisting of:

[0037] alkoxy compounds of one thru seven carbon atoms,

[0038] carbonate,

[0039] methyl, sec-butyl and t-butyl carbanions,

[0040] tri(alkyl)amines where the alkyl group is from 1 thru 4 carbonatoms,

[0041] conjugate base of the carbamate (II),

[0042] DBU,

[0043] DBN,

[0044] N-methyl-piperidine,

[0045] N-methyl morpholine,

[0046] 2,2,2-trichloroethoxide and Cl₃C—CH₂—O⁻; most preferred bases arewhere the base is alkoxy of four or five carbon atoms. It is preferredthat the four and five carbon alcohol bases be t-amylate or t-butoxide.Sodium or potassium bases in combination with a lithium salt (such aslithium chloride or lithium bromide) can be used forming the lithiumcation and base in situ. The nature of the solvent is not critical.Operable solvents include cyclic ethers such as THF, amides such as DMFand DMAC, amines such as triethylamine, acetonitrile, and alcohols suchas t-amyl alcohol and t-butyl alcohol. The choice of solvent depends onthe solubilty of the carbamate (IX) and the three carbon unit (VIIIA,VIIIb or VIIIC) as is known to those skilled in the art.

[0047] CHART E discloses the reaction of the carbamate (IX) with eitherthe (S)-phthalimide alcohol (IVC) or the (S)-phthalimide epoxide (IVD)to produce the (S)-ring-phthalimide (XI) which is then converted to thecorresponding (S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) product which haspharmaceutical utility.

[0048] CHART F discloses the reaction of the carbamate (IX) with either(S)-protected alcohol (IVA) or (S)-imine of glydidylamine (IVB) toproduce the corresponding (S)-oxazolidinone protected compound (XII)which is then transformed to the (S)-oxazolidinone free amine (XIII)which is then acylated as discussed above to produce the(S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) product which has pharmaceuticalutility. These processes are the same as those for CHARTS D and E or arewell known to those skilled in the art.

[0049] CHART G discloses the reaction of the carbamate (IX) directlywith the (S)-3-carbon amino alcohol (V) to give the (S)-oxazolidinonefree amine (XIII) which is then acylated to give the(S)-oxazolidinone-CH₂—NH—CO—R_(N) (X). These processes are preformed inthe same manner as previously disclosed.

[0050] CHART H discloses the reaction of teh isocynate (XIV) with(S)-secondary alcohol (VIIIA) to give the (S)-intermediate (XV) which isthen transformed to the (S)-oxazolidinone-CH₂—NH—CO—R_(N) (X), seeEXAMPLES 6, 8 and 9.

[0051] CHART I discloses a reaction analogous to that of CHART E.Whereas the process of CHART E used a carbamate (IX), the process ofCHART I uses an isocynate (XIV).

[0052] The (S)-oxazolidinone-CH₂—CO-amines (X) are known to be useful asantibiotic pharmaceuticals.

Definitions and Conventions

[0053] The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

I. Conventions for Formulas and Definitions of Variables

[0054] The chemical formulas representing various compounds or molecularfragments in the specification and claims may contain variablesubstituents in addition to expressly defined structural features. Thesevariable substituents are identified by a letter or a letter followed bya numerical subscript, for example, “Z₁” or “R_(i)” where “i” is aninteger. These variable substituents are either monovalent or bivalent,that is, they represent a group attached to the formula by one or twochemical bonds.

[0055] For example, a group Z₁ would represent a bivalent variable ifattached to the formula CH₃—C(=Z₁)H. Groups R_(i) and R_(j) wouldrepresent monovalent variable substituents if attached to the formulaCH₃—CH₂—C(R_(i))(R_(j))—H. When chemical formulas are drawn in a linearfashion, such as those above, variable substituents contained inparentheses are bonded to the atom immediately to the left of thevariable substituent enclosed in parenthesis. When two or moreconsecutive variable substituents are enclosed in parentheses, each ofthe consecutive variable substituents is bonded to the immediatelypreceding atom to the left which is not enclosed in parentheses. Thus,in the formula above, both R_(i) and R_(j) are bonded to the precedingcarbon atom. Also, for any molecule with an established system of carbonatom numbering, such as steroids, these carbon atoms are designated asC_(i), where “i” is the integer corresponding to the carbon atom number.For example, C₆ represents the 6 position or carbon atom number in thesteroid nucleus as traditionally designated by those skilled in the artof steroid chemistry. Likewise the term “R₆” represents a variablesubstituent (either monovalent or bivalent) at the C₆ position.

[0056] Chemical formulas or portions thereof drawn in a linear fashionrepresent atoms in a linear chain. The symbol “-” in general representsa bond between two atoms in the chain. Thus CH₃—O—CH₂—CH(R_(i))—CH₃represents a 2-substituted-1-methoxypropane compound. In a similarfashion, the symbol “═” represents a double bond, e.g.,CH₂═C(R_(i))—O—CH₃, and the symbol “≡” represents a triple bond, e.g.,HC≡C—CH(R_(i))—CH₂—CH₃. Carbonyl groups are represented in either one oftwo ways: —CO— or —C(═O)—, with the former being preferred forsimplicity.

[0057] Chemical formulas of cyclic (ring) compounds or molecularfragments can be represented in a linear fashion. Thus, the compound4-chloro-2-methylpyridine can be represented in linear fashion byN^(#)═C(CH₃)—CH═CCl—CH═C^(#)H with the convention that the atoms markedwith an asterisk (#) are bonded to each other resulting in the formationof a ring. Likewise, the cyclic molecular fragment,4-(ethyl)-1-piperazinyl can be represented by—N^(#)—CH₂)₂—N(C₂H₅)—CH₂—C^(#)H₂.

[0058] A rigid cyclic (ring) structure for any compounds herein definesan orientation with respect to the plane of the ring for substituentsattached to each carbon atom of the rigid cyclic compound. For saturatedcompounds which have two substituents attached to a carbon atom which ispart of a cyclic system, —C(X₁)(X₂)— the two substituents may be ineither an axial or equatorial position relative to the ring and maychange between axial/equatorial. However, the position of the twosubstituents relative to the ring and each other remains fixed. Whileeither substituent at times may lie in the plane of the ring(equatorial) rather than above or below the plane (axial), onesubstituent is always above tie other. In chemical structural formulasdepicting such compounds, a substituent (X₁) which is “below” anothersubstituent (X₂) will be identified as being in the alpha (a)configuration and is identified by a broken, dashed or dotted lineattachment to the carbon atom, i.e., by the symbol “- - - ” or “ . . .”. The corresponding substituent attached “above” (X₂) the other (X₁) isidentified as being in the beta (β) configuration and is indicated by anunbroken line attachment to the carbon atom.

[0059] When a variable substituent is bivalent, the valences may betaken together or separately or both in the definition of the variable.For example, a variable R_(i) attached to a carbon atom as —C(═R_(i))—might be bivalent and be defined as oxo or keto (thus forming a carbonylgroup (—CO—) or as two separately attached monovalent variablesubstituents α-R_(i-j) and β-R_(i-k). When a bivalent variable, R_(i),is defined to consist of two monovalent variable substituents, theconvention used to define the bivalent variable is of the form“α-R_(i-j):β-R_(i-k)” or some variant thereof. In such a case bothα-R_(i-j) and β-R_(i-k) are attached to the carbon atom to give—C(α-R_(i-j))(β-R_(i-k))—. For example, when the bivalent variable R₆,—C(═R₆)— is defined to consist of two monovalent variable substituents,the two monovalent variable substituents are α-R₆₋₁:β-R₆₋₂, . . .α-R₆₋₉:β-R₆₋₁₀, etc, giving —C(α-R₆₋₁)(β-R₆₋₂)—, . . .—C(α-R₆₋₉)(β-R₆₋₁₀)—, etc. Likewise, for the bivalent variable R₁₁,—C(═R₁₁)—, two monovalent variable substituents are α-R₁₁₋₁:β-R₁₁₋₂. Fora ring substituent for which separate a and B orientations do not exist(e.g. due to the presence of a carbon carbon double bond in the ring),and for a substituent bonded to a carbon atom which is not part of aring the above convention is still used, but the α and β designationsare omitted.

[0060] Just as a bivalent variable may be defined as two separatemonovalent variable substituents, two separate monovalent variablesubstituents may be defined to be taken together to form a bivalentvariable. For example, in the formula —C₁(R_(i))H—C₂(R_(j))H— (C₁ and C₂define arbitrarily a first and second carbon atom, respectively) R_(i)and R_(j) may be defined to be taken together to form (1) a second bondbetween C₁ and C₂ or (2) a bivalent group such as oxa (—O—) and theformula thereby describes an epoxide. When R_(i) and R_(j) are takentogether to form a more complex entity, such as the group —X—Y—, thenthe orientation of the entity is such that C₁ in the above formula isbonded to X and C₂ is bonded to Y. Thus, by convention the designation “. . . R_(i) and R_(j) are taken together to form —CH₂—CH₂—O—CO— . . . ”means a lactone in which the carbonyl is bonded to C₂. However, whendesignated “ . . . R_(j) and R_(i) are taken together to form—CO—O—CH₂—CH₂— the convention means a lactone in which the carbonyl isbonded to C₁.

[0061] The carbon atom content of variable substituents is indicated inone of two ways. The first method uses a prefix to the entire name ofthe variable such as “C₁-C₄”, where both “1” and “4” are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variable by a space. Forexample, “C₁-C₄ alkyl” represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Whenever this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂-C₄ alkoxycarbonyl describes a group CH₃—CH₂)_(n)—O—CO— where nis zero, one or two. By the second method the carbon atom content ofonly each portion of the definition is indicated separately by enclosingthe “C_(i)-Cj” designation in parentheses and placing it immediately (nointervening space) before the portion of the definition being defined.By this optional convention (C₁-C₃)alkoxycarbonyl has the same meaningas C₂-C₄ alkoxy-carbonyl because the “C₁-C₃” refers only to the carbonatom content of the alkoxy group. Similarly while both C₂-C₆ alkoxyalkyland (C₁-C₃)alkoxy(C₁-C₃)alkyl define alkoxyalkyl groups containing from2 to 6 carbon atoms, the two definitions differ since the formerdefinition allows either the alkoxy or alkyl portion alone to contain 4or 5 carbon atoms while the latter definition limits either of thesegroups to 3 carbon atoms.

[0062] When the claims contain a fairly complex (cyclic) substituent, atthe end of the phrase naming/designating that particular substituentwill be a notation in (parentheses) which will correspond to the samename/designation in one of the CHARTS which will also set forth thechemical structural formula of that particular substituent.

II. Definitions

[0063] All temperatures are in degrees Centigrade.

[0064] TLC refers to thin-layer chromatography.

[0065] PLC refers to high pressure liquid chromatography.

[0066] THF refers to tetrahydrofuran.

[0067] * indicates that the carbon atom is an enantiomeric carbon in the(S) configuration

[0068] # indicates that the atoms marked with a (#) are bonded to eachother resulting in the formation of a ring.

[0069] RING is defined in CHART J as the oxazolidinone ring, a.2,5-disubstituted-oxazolidinone.

[0070] DMF refers to dimethylformamide.

[0071] DMAC refers to dimethylacetamide.

[0072] Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

[0073] IR refers to infrared spectroscopy.

[0074] CMR refers to C-13 magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) downfield from TMS.

[0075] NMR refers to nuclear (proton) magnetic resonance spectroscopy,chemical shifts are reported in ppm (8) downfield fromtetramethylsilane.

[0076] TMS refers to trimethylsilyl.

[0077] -φ refers to phenyl (C₆H₅).

[0078] [β]D²⁵ refers to the angle of rotation of plane polarized light(specific optical rotation) at 25° with the sodium D line (589A).

[0079] MS refers to mass spectrometry expressed as m/e, m/z ormass/charge unit. [M+H]+refers to the positive ion of a parent plus ahydrogen atom. EI refers to electron impact. CI refers to chemicalionization. FAB refers to fast atom bombardment.

[0080] Pharmaceutically acceptable refers to those properties and/orsubstances which are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

[0081] When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

[0082] When the solubility of a solid in a solvent is used the ratio ofthe solid to the solvent is weight/volume (wt/v).

EXAMPLES

[0083] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, practice the presentinvention to its fullest extent. The following detailed examplesdescribe how to prepare the various compounds and/or perform the variousprocesses of the invention and are to be construed as merelyillustrative, and not limitations of the preceding disclosure in any waywhatsoever. Those skilled in the art will promptly recognize appropriatevariations from the procedures both as to reactants and as to reactionconditions and techniques.

[0084] PREPARATION 1 3-Fluoro-4-morpholinylaniline

[0085] 3,4-Difluoronitrobenzene (25.196 g, 158.38 mmol) is added to amixture of morpholine (60.0 ml, 688 mmol, 4.34 eq) in THF (30 ml) at−14°. The mixture is permitted to warm to 10° then maintained at 10-13°for 1 hr. A mixture of citric acid monohydrate (75 g, 357 mmol, 2.25 eq)in water (365 ml) is added with concomitant exotherm to 28°. The phasesare separated and the aqueous phase is washed with toluene (95 ml). Theorganic phase is washed with water (315 ml) and concentrated underreduced pressure. Toluene (46 ml) and methanol (60 ml) are addedfollowed by palladium on Carbon (5%o, 50% water wet, 3.1603 g, 0.7426mmol, 0.00469 eq) and the mixture sealed in a Parr shaker. Hydrogenpressure (40 psi) is applied and maintained while agitating for 42 min.The catalyst is then removed by filtration under reduced pressure andwashed with toluene (60 ml). Heptane (150 ml) is added to the filtrateand the resultant slurry concentrated under reduced pressure. Heptane(300 ml) is added and the precipitate collected by filtration underreduced pressure and washed with heptane and dried to give the titlecompound, HPLC (stationary phase is 4.6×250 mm zorbax RX C-8 column;mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) andacetic acid (1.30 ml) and water of sufficient amount to make 1,000 ml;flow rate=3.0 ml/min; UV detection at 254 nm) RT=1.08 min, >99.3 area);NMR (Pyridine-D₅) 2.95-2.98, 3.80-3.83, 5.38, 6.68, 6.78 and 6.90 δ; CMR(Pyridine-D₅) 52.43, 67.33, 103.31, 110.63, 121.29, 130.80, 146.23 and157.72 δ.

[0086] PREPARATION 2 N-Carbomethoxy-3-fluoro-4-morpholinylaniline (IX)

[0087] 3,4-Difluoronitrobenzene (PREPARATION 1, 24.967 g, 156.94 mmol)is added to a mixture of morpholine (60.0 ml, 688 mmol, 4.38 eq) in THF(30 ml) at −6°. The mixture is permitted to warm to 10° over 2 hrs thenmaintained at 10° for ½ hr. A mixture of citric acid monohydrate (75 g,357 mmol, 2.27 eq) in water (365 ml) is added with concomitant exothermto 28°. The phases are separated and the aqueous washed with toluene (95ml). The organic phases are washed with water (315 ml), the aqueous backwash extracted with toluene (95 ml) and concentrated under reducedpressure. Toluene (76 ml) and methanol (60 ml) are added followed bypalladium on carbon (5%, 50% water wet, 3.1370 g, 0.7371 mmol, 0.00470eq) and the mixture sealed in a Parr shaker. Hydrogen pressure (40 PSI)is applied and maintained while agitating for 4.5 hrs. The catalyst isthen removed by filtration under reduced pressure and washed withtoluene (100 ml). The mixture is cooled to 2° and a mixture of aqueouspotassium carbonate (47%, 17.1 ml, 85 mmol, 0.54 eq) and water (150 ml)is added. Methyl chloroformate (16.4 ml, 212 mmol, 1.35 eq) is thenadded while maintaining the temperature at about 3-3.5°. The resultantslurry is permitted to warm to 20-25° and stirred 17 hrs. The mixture iswarmed to 75° to give a solution, then cooled to 46°, heptane (333 ml)added, then the mixture cooled to 0°, the precipitate collected byfiltration with reduced pressure, washed with heptane (100 ml cooled to5°) then water (230 ml cooled to 5°) and dried to give the titlecompound, TLC (silica gel; methanol/methylene chloride, 5/95) R_(f)=0.74(one spot); NMR (CDCl₃) 3.03, 3.76, 3.86, 6.75, 6.87, 6.98, 7.27; CMR(CDCl₃) 51.18, 52.42, 67.03, 107.81, 114.56, 119.00, 133.25, 135.77,154.07, 155.70,

[0088] PREPARATION 3 3-Fluoro-4-morpholinylphenylisocyanate (XIV)

[0089] A mixture of 3-Fluoro-4-morpholinylaniline (PREPARATION 1, 12.01g, 61.21 mmol) in methylene chloride (100 ml) is added to a mixture ofphosgene (1.93 M in toluene, 63.4 ml, 122.4 mmol, 2.00 eq) inp-chlorotoluene (60 ml) over 15 min, a while maintaining the temperaturefrom about −12 to 3°. The material is rinsed in with methylene chloride(30 ml). The mixture is then warmed to 130° under atmospheric pressurewith concomitant distillation of methylene chloride, phosgene, tolueneand hydrogen chloride gas into a caustic scrubber. The mixture is cooledto 25° and filtered. The precipitate is washed with methylene chloride(3×15 ml). The filtrate is concentrated under reduced pressure. Heptane(200 ml) is added to the concentrated filtrate and the resultant slurrycooled to −32°. The product is collected by filtration with reducedpressure, washed with heptane cooled to −30°, and dried in a nitrogenstream to give the title compound, HPLC (stationary phase is 4.6×250 mmzorbax RX C-8 column; mobile phase is acetonitrile (650 ml),triethylamine (1.85 ml) and acetic acid (1.30 ml) and water ofsufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detectionat 254 nm) RT=1.08 min. Upon derivatizing asN-carbomethoxy-3-fluoro-4-morpholinylaniline by dissolving in methanol;NMR (CDCl₃) 3.05, 3.86 and 6.78-6.89 δ; CMR (CDCl₃) 50.90, 66.89,113.11, 119.15, 120.83, 124.67, 127.65, 138.06 and 155.40 δ; MS (EI),m/z (relative intensity) 222 (37) and 164 (100).

Example 1 (S)-1-Amino-3-chloro-2-propanol hydrochloride (V)

[0090] (S)-Epichlorohydrin (III, 44.978 g, 486.1 mmol, 98.9%enantiomeric excess, 99.3 chemical % purity) is added to a mixture ofbenzaldehyde (I, 50.0 ml, 492 mmol, 1.012 eq), ethanol (163 ml) andaqueous ammonia (II, 29.8 wt %, 50 ml, 787.4 mmol, 1.62 eq) at 18° over10 min with an exotherm to 22°. The reaction mixture is permitted toexotherm to 34° over 1.5 hrs, warmed to 42°, stirred at 20-25° for 20.5hrs, then warmed to 74° and immediately allowed to cool. The mixture isconcentrated under reduced pressure to give(S)-1-benzalimino-3-chloro-2-propanol (IVA). Water (382 ml) andhydrochloric acid (37.7 wt %, 76.2 ml, 938 mmol, 1.93 eq) is added tothe concentrate and the mixture stirred at 20-25° for 2 hrs. Toluene(150 ml) is added and the phases are separated. The organic phase iswashed with water (15 ml) and the combined aqueous washed with toluene(2×150 ml), back extracting each organic extract with water (15 ml). Thecombined aqueous extracts are concentrated under reduced pressure.Ethanol (200 ml) is added to the concentrate and the mixtureconcentrated under reduced pressure. Ethanol (300 ml) is added to theconcentrate and the mixture warmed to reflux. The mixture is cooled to−30° and the precipitate collected by filtration with reduced pressure,washed with −30° ethanol (2×60 ml) and dried in a nitrogen stream togive a white solid, mp=132-141°; NMR (CD₃OD) 2.96, 3.21, 3.57-3.64 and4.03-4.09 δ; CMR (CD₃OD) 43.52, 46.91 and 68.72 δ; MS (CI, NH₃), M/Z(relative intensity) 129 (24), 127 (69), 112 (61), 110 (100); [a]²⁵_(D)=−22 (c=1.00, H₂O).

Example 2 (S)-1-Acetamido-2-hydroxy-3-chloropropane (VIIIA)

[0091] Triethylamine (10.5 mL 75.3 mmol, 1.11 eq) is added to a slurryof (S)-1-amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1, 9,938 g,68.059 mmol) in THF (80 ml) at −40° and the mixture stirred for 5 min at−40°. Acetic anhydride (6.78 ml, 71.86 mmol, 1.056 eq) is then added at−40° and the mixture allowed to warm to 20-25° over 1.5 hrs. Theprecipitate is removed by filtration with reduced pressure and washedwith THF. The filtrate is treated with magnesol (5.69 g), which isremoved by filtration with reduced pressure and washed with THF (2×60ml). The filtrate is then concentrated under reduced pressure. Theconcentrate is purified by flash chromatography (silica gel; elutingwith a gradient of 75-100% ethyl acetate/cyclohexane) to give the titlecompound, NMR (CDCl₃) 2.03, 3.32, 3.50-3.57, 3.55, 3.91-4.13, 5.01 and7.09 8; CMR (CDCl₃) 23.00, 43.31, 46.52, 70.65 and 172.40 δ; MS (CI,NH₃), M/Z (relative intensity), 171 (41.6), 169 (100), 154 (22.4), 152(48.1); [a]²⁵ _(D=−)7.44 (c=1.00, H₂O).

Example 3 (±)-1-Acetamido-2-acetoxy-3-chloropropane (VIIIC)

[0092] Acetic anhydride (13 ml) is added to a thin slurry of(±)-1-amino-3-chloro-2-propanol hydrochloride ((±)-V, EXAMPLE 5, 5.0110g, 34.317 mmol) in pyridine (20 ml) while maintaining the temperature inthe range of 20-50°. The mixture is stirred at 20-25° for 18 hours, thenwater (14 ml) is added with an exotherm to 65°. The mixture isconcentrated under reduced pressure and water (50 ml) is added. The pHis adjusted to 0.89 with hydrochloric acid (37.7%, 1.467 g, 15.17 mmol,0.442 eq) at 0°. The mixture is extracted with methylene chloride (4×50ml), the extracts dried over sodium sulfate and concentrated underreduced pressure. Ethyl acetate (20 ml) and heptane (20 ml) are added,thc mixture seeded, then heptane (40 ml) is added to the resultantslurry. The precipitate is collected by filtration with reducedpressure, washed with heptane and dried to give a the title compound,mp=68.0-69.5°; TLC (silica gel; ethyl acetate, iodine char) R_(f)=0.39(one spot); NMR 2.00, 2.21, 3.52, 3.62, 3.70, 5.10 and 6.33 δ; CMR20.93, 23.10, 40.47, 43.53, 71.95, 170.45 and 170.71 δ; MS (CI, NH₃) m/z(relative intensity) 213 (36), 211 (100), 196 (18) and 194 (53).

Example 4 (S)-1-Phthalimido-3-chloro-2-propanol (S)-(IVC)

[0093] (S)-epichlorohydrin (III, 98.9% enantiomerically pure, 99.3chemical % purity, 4.9605 g, 53.61 mmol) is added to a slurry ofpotassium phthalimide (VI, 5.031 g, 27.161 mmol, 0.507 eq) andphthalimide (VI, 11.836 g, 80.45 mmol, 1.5006 eq) in DMF (32 ml) and themixture stirred at 50° for 4.5 hrs. The mixture is added to methylenechloride (50 ml) and water (50 ml) added. The solids are removed byfiltration with reduced pressure and washed with methylene chloride (20ml). The phases are separated in the filtrate and the aqueous washedwith methylene chloride (50 ml). The combined organics were washed withwater (50 ml) and the aqueous backextraceted with methylene chloride (50ml) after adding water (25 ml). The combined organics are dried oversodium sulfate and saturated with hydrogen chloride gas at 6°. Water(100 ml) is added and the phases separated. The aqueous phase is washedwith methylene chloride (2×50 ml) and the combined organic phases aredried over sodium sulfate. The organic phase is concentrated underreduced pressure and toluene added (77 ml). The mixture is concentratedunder reduced pressure to 31 g net weight and toluene (50 ml) andheptane (75 ml) added. The solids are filtered off and washed withtoluene/heptane (1/1, 20 ml). The filtrate is concentrated under reducedpressure to 17 g net weight, heptane (100 ml) added and the mixtureconcentrated under reduced pressure to 15 g net weight. Heptane (100 ml)and methylene chloride (100 ml) is added and the mixture concentratedunder reduced pressure to 130 g net weight. The solids are filtered offand washed with heptane/methylene chloride (2/1, 3×15 ml). The filtrateis concentrated under reduced pressure to 11 g net weight and toluene(90 ml) then heptane (400 ml) added. The resultant slurry is then cooledto −20° and the product collected by filtration with reduced pressure,washed with heptane and dried to give a crude solid. Flashchromatography of the crude solid (silica gel; eluting with a gradientof 15-45% ethyl acetatelcyclohexane) gives the title compound as ananalytical sample, NMR 3.11, 3.62, 3.68, 3.87, 3.95, 4.14-4.20,7.70-7.76 and 7.82-7.88 δ; CMR 41.61, 47.27, 69.68, 123.53, 131.83,134.26 and 168.65 δ; MS (CI, NH₃), M/Z (relative intensity) 259 (1.4),257 (17), 242 (0.11), 240 (0.31), 221 (100); [α]²⁵ _(D)=−33 (C=0.712,CHCl₃). NMR of the mosher ester derivative showed the product to have anenantiomeric purity of 96.2% upon comparison to the NMR of the mosherester of the racemate.

Example 5 (±)-1-Amino-3-chloro-2-propanol hydrochloride (+)-(V)

[0094] A slurry of (±)-1-phthalimido-3-choro-2-propanol (IVC, 40.018 g,166.98 mmol) in hydrochloric acid (37.5 wt %, 79 ml, 968 mmol, 5.80 eq)and water (82 ml) is stirred at 109° for 5 hrs. The mixture is cooled to22° and the precipitate is removed by filtration with reduced pressureand washed with water (40 ml). The filtrate is concentrated underreduced pressure to 26 g net weight and ethanol (100 ml) added. Themixture is warmed to 75° to give a solution then cooled to −12° and theresultant precipitate collected by filtration with reduced pressure,washed with ethanol cooled to −12° and dried to give the title compound,mp=101-104°; NMR (CD₃OD) 2.96, 3.21, 3.57-3.64 and 4.03-4.09 δ; CMR(CD₃OD) 43.54, 46.95 and 68.71 δ; MS (CI, NH₃), M/Z (relative intensity)129 (12), 127 (39), 112 (56), 110 (100).

Example 6(S)—N-Carbo(1′-acetamido-3′-chloro-2′-propoxy)-3-fluoro-4-morpholinylaniline((S)-XV)

[0095] Acetyl chloride (0.3297 g, 4.20 mmol, 1.019 eq) is added to aslurry of (S)-1-Amino-3-chloro-2-propanol hydrochloride (V, EXAMPLE 1,0.6020 g, 4.12 mmol) and triethylamine (1.26 ml, 9.04 mmol, 2.19 eq) inacetonitrile (70 ml) at −40°.

[0096] The mixture is then warmed to 3-6°, stirred several hours, warmedto 22° and 3-fluoro-4-morpholinylphenylisocyanate (IV, PREPARATION 3,1.0152 g, 4.568 mmol, 1.108 eq) added. The mixture is warmed to 64°,stirred 10 min, then concentrated under reduced pressure to about 25 ml.3-Fluoro4-morpholinylphenylisocyanate (XIV, 0.0907 g, 0.408 mmol,0.09887 eq) is then added and the mixture stirred at 65° for 17 hrs.Pentanol (1.34 ml, 12.33 mmol, 2.99 eq) is added and the mixture stirredat 65° for 1.7 hrs. Water (5 ml) is added and the mixture cooled to −4°.Water (38 ml) and heptane (30 ml) were added and the mixture warmed to15° and stirred 1 hr. The resulting precipitate is collected byfiltration under reduced pressure and washed with heptane and water anddried to give a solid. The filtrate is concentrated under reducedpressure to 50 ml total volume and the precipitate collected byfiltration under reduced pressure, washed with water (10 ml) and heptane(10 ml) and dried to give a brown solid. A portion of the first solids(0.9404 g) and the second solids (0.4018 g) is dissolved in acetonitrile(15 ml) at 76°, then cooled to −10° and the precipitate collected byfiltration under reduced pressure, washed with acetonitrile cooled to−10° and dried to give the title compound, HPLC (stationary phase is4.6×250 mm zorbax RX C-8 column; mobile phase is acetonitrile (650 ml),triethylamine (1.85 ml) and acetic acid (1.30 ml) and water ofsufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detectionat 254 nm)=92.3 area to).

Example 7(S)—N-Carbo(1′-acetamido-3′-chloro-2′-propoxy)-3-fluoro-4-morpholinylaniline((S)-XV)

[0097] A mixture of (S)-1-acetamido-3-chloro-2-propanol (VIIIA, EXAMPLE2, 1.024 g, 6.754 mmol, 1.00 eq) and3-fluoro-4-morpholinylphenylisocynate (XIV, PREPARATION 3, 1.6756 g,7.539 mmol, 1.12 eq) in acetonitrile (25 ml) is stirred at 60° for 46hrs. The resultant slurry is cooled to −13°, the precipitate collectedby filtration with reduced pressure, washed with acetonitrile cooled to−13° C. (20 ml) and dried to give the title compound, NMR (DMSO-D6)1.83, 2.93, 3.2-3.5, 3.73, 3.78, 3.88, 4.99, 6.97, 7.20, 7.36, 8.07 and9.80 δ; CMR (DMSO-D6) 22.42, 39.6, 44.71, 50.77, 66.15, 71.81, 106.49,114.23, 119.21, 134.18, 134.59, 152.57, 154.65 and 169.67 δ; MS (CI,NH₃), M/Z (relative intensity) 376 (27.0), 374 (85.9), 339 (12.2), 338(80.8) and 223 (17.2); [a]²⁵ _(D)=−4.08 (C=0.930, DMF).

Example 8(S)-N-[[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide((S)-X)

[0098] A solution of sodium t-butoxide (0.0854 g, 0.889 mmol, 1.05 eq)in ethanol (0.60 ml) is added to a slurry of(S)—N-carbo(1′-acetamido-3′-chloro-2′-propoxy)-3-fluoro-4-morpholinylanline((S)-(XV), EXAMPLE 7, 0.3176 g, 0.850 mmol) in ethanol (4.6 ml) at 65°and is rinced in with ethanol (0.50 ml). The mixture is stirred 28 minand cooled to 0°. Citric acid monohydrate (0.1943 g, 0.925 mmol, 1.09eq) is added and the resulting slurry concentrated under reducedpressure to 1.30 g net weight. Water (10 ml) and methylene chloride (10ml) is added, the phases separated and the aqueous phase washed withmethylene chloride (2×10 ml). The combined organic phases are dried oversodium sulfate and concentrated under reduced pressure to a solid. Thesolid is dissolved in ethyl acetate (8.4 ml) at 70°, solution cooled to50°, seeded, further cooled to −28°, the precipitate collected byfiltration with reduced pressure, washed with ethyl acetate previouslycooled to −30° and dried to give the title compound, HPLC (100.7 wt %,99.9 area %; NMR (CDCl₃) 2.04, 3.04, 3.65, 3.77, 3.86, 4.02, 4.74-4.82,6.80, 6.91, 7.06 and 7.42 δ; CMR (CDCl₃) 22.99, 41.88, 47.64, 50.96,66.94, 72.08, 107.55, 113.98, 118.83, 132.93, 136.55, 154.55, 155.44 and171.40 3; MS (EI), M(Z (relative intensity) 337 (16.9), 293 (74.4), 234(37.5), 209 (100); [α]²⁵ _(D)=−15.8 (C=0.903, ethanol).

Example 9(S)-N-[[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide(IV)

[0099] Following the general procedure of EXAMPLE 8 and makingnon-critical variations the title compound is obtained, NMR 2.02, 3.04,3.65, 3.77, 3.86, 4.02, 4.74-4.82, 6.74, 6.91, 7.06 and 7.42 o); CMR23.02, 41.89, 47.65, 50.97, 66.87, 72.06, 107.48, 114.01, 118.76,132.85, 136.48, 154.52, 155.38 and 171.34 δ; MS (CI, NH₃), M/Z (relativeintensity) 338 (100), 294 (86.8); [a]²⁵ _(D)=−15.2 (C=0.783, ethanol).

Example 10 (±)-N-(2-Hydroxy-3-chloro)acetamide (VIIIA)

[0100] To a slurry of (±)-1-Amino-3-chloro-2-propanol hydrochloride (V,EXAMPLE 5, 47.71 g, 326.74 mmol) in THF (381 ml) at −40 is addedtriethylamine (36.496 g, 360.67 mmol, 1.104 eq) followed by aceticanhydride (35.007 g, 342.90 mmol, 1.049 eq) while maintaining thetemperature at <−30°. The mixture is stirred 15 min at −30°, thenallowed to warm to 20° over 1 hr. The mixture is stirred at 20-25° for 3hours, then the precipitate is removed by vacuum filtration through amedium frit and washed with THF (175 ml). The filtrate is concentratedunder reduced pressure to and toluene (195 ml) added. The mixture isconcentrated under reduced pressure to and toluene (250 ml) is added.The mixture is concentrated under reduced pressure and toluene (250 ml),methanol (40 ml) and ethyl acetate (10 ml) added. The mixture is cooledto −20°, seeded, heptane (200 ml) added at −30°, the mixture cooled to−33° and the precipitate collected by vacuum filtration, washed withheptane (100 ml) and dried. This solid (44.818 g) is dissolved intoluene (250 ml) and methanol (120 ml) and concentrated under reducedpressure. The mixture is cooled to −30°, seeded and heptane (180 ml) isadded the precipitate collected by vacuum filtration at −30°, washedwith heptane (100 ml) and dried to give a solid, mp=50.1-52.30; TLC(silica gel; methanol/methylene chloride (5/95), iodine char) R_(f)=0.23(single more polar spot identified as 1.1 wt % triethylammonium acetateby NMR); NMR (CDCl₃) 2.03, 3.33, 3.54, 3.95, 4.73 and 6.93 δ; CMR(CDCl₃) 23.01, 43.32, 46.48, 70.72 and 172.37 δ; MS (CI, NH₃) m/z(relative intensity) 154 (34), 152 (100).

Example 11 (±)-Glycidylacetamide (VIIIB)

[0101] To a solution of (±) 1-acetamido-3-chloro-2-propanol (V, EXAMPLE10, 10.344 g, 68.24 mmol) in tetrahydrofuran (21 ml) at −40° Is added asolution of potassium t-butoxide in THF (1.0 M, 65 ml, 65 mmol, 0.95eq). The mixture was warmed to −20° and stirred for 15 min then cooledto −37° and silica gel (18.5 g) is added. The solids are removed byvacuum filtration and washed with ethyl acetate (1,000 ml). The filtrateis concentrated and the precipitate removed by vacuum filtration. Thefiltrate is concentrated and heptane (50 ml) is added. The mixture isseeded, sonicated, and the precipitate collected by-vacuum filtration,washed with heptane and dried in a nitrogen stream to give the titlecompound, mp=34.6-37.3°; TLC (silica gel; methanol/methylene chloride(5/95), iodine char) R_(f)=0.24; NMR 2.01, 2.59, 2.80, 3.10-3.13,3.24-3.29, 3.7-3.9, 6.19 8; CMR 23.07, 40.67, 45.19, 50.61 and 170.54 δ.

Example 12(±)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide(X)

[0102] To a solution of (±)-glycidylacetamide (VIIIB, EXAMPLE 11, 0.1571g, 1.365 mmol) in THF (1.63 ml) at −78° is addedN-carbomethoxy-3-fluoro-4-morpholinylaniline (IX, PREPARATION 2, 0.4358g, 1.71 mmol, 1.26 eq) and lithium t-butoxide (0.1267 g, 1.583 mmol,1.16 eq). The reaction mixture is then stirred at 0 to 11° for 17.5 hrsat which point HPLC showes an 80% yield of(±)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide(retention time=0.97 min; method B; Stationary phase: 4.6×250 mm ZorbaxRX C-8 column; mobile phase: 650 ml acetonitrile, 1.85 ml triethylamine,1.30 ml acetic acid, water sufficient to make 1000 ml; flow rate: 3.0ml/min; UV detection at 254 nm). The title compound is isolated by meansknown to those skilled in the art.

Example 13(S)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide(X)

[0103] Step A: (S)—N-(2-Hydroxy-3-chloro)acetamide (VIIIA)

[0104] Following the general procedure of EXAMPLE 10 and makingnon-critical variations but starting with(S)-1-amino-3-chloro-2-propanol hydrochloride (V,

EXAMPLE 1), the title compound is obtained.

[0105] Step B: (S)-Glycidylacetamide (VIIIB)

[0106] Following the general procedure of EXAMPLE 11 and makingnon-critical variations but starting with(S)—N-(2-Hydroxy-3-chloro)acetamide (VIIIA, Step A), the title compoundis obtained.

[0107] Step C:(S)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide(X)

[0108] Following the general procedure of EXAMPLE 12 and making noncritical variations but starting with (S)-Glycidylacetamide (VIIIB, StepB), the title compound is obtained.

Example 14 (S)-1-Acetamido-2-acetoxy-3-chloropropane (VIIIC)

[0109] Following the general procedure of EXAMPLE 3 and making noncritical variations but starting with (S)-1-Amino-3-chloro-2-propanolhydrochloride (V, EXAMPLE 1), the title compound is obtained.

Example 15 (S)-1-Amino-3-chloro-2-propanol hydrochloride (S)-(V

[0110] Following the general procedure of EXAMPLE 5 and makingnon-critical variations but using (S)-1-phthalimido-3-chloro-2-propanol(S)-(IVC, EXAMPLE 4) the title compound is obtained.

1. An (S)-secondary alcohol of formula (VIIIA)X₂—CH₂—C*H(OH)—CH₂—NH—CO—R_(N)  (VIIIA) where: (I) R_(N) is C₁-C₅ alkyl;(II) X₂ is: (A) —Cl, (B) —Br, (C) p-CH₃-φ-SO₂—, (D) m-NO_(2-φ-SO) ₂—, 2.An (S)-secondary alcohol (VIIIA) according to claim 1 where R_(N) is C₁alkyl.
 3. An (S)-secondary alcohol (VIIIA) according to claim 1 where X₂is —Cl.
 4. An (S)-secondary alcohol (VIIIA) according to claim 1 whichis selected from the group consisting of(S)1-acetamido-2-hydroxy-3-chloropropane.
 5. An (S)-epoxide of formula(VIIIB) —O^(#)—CH₂—C*^(#)H—CH₂—NH—CO—R_(N)  (VIIIB) where: (I) whereR_(N) is C₁-C₅ alkyl; (II) where # indicates that the atoms marked witha (^(#)) are bonded to each other resulting in the formation of a ring.6. An (S)-epoxide (VIIIB) according to claim 5 where R_(N) is C₁ alkyl.7. An (S)-epoxide (VIIIB) according to claim 5 which is selected fromthe group consisting of (S)-glycidylacetamide.
 8. An (S)-ester offormula (VIIIC) X₂—CH₂—C*H(O—CO—R_(N))—CH₂—NH—CO—R_(N)  (VIIIC) where:(I) where R_(N) is C₁-C₅ alkyl; (II) where X₂ is: (A) —Cl, (B) —Br, (C)p-CH₃-φ-SO₂—, (D) m-NO₂-φ-SO₂—.
 9. An (S)-ester (VIIIC) according toclaim 8 where R_(N) is C₁ alkyl.
 10. An (S)-ester (VIIIC) according toclaim 8 where X₂ is —Cl.
 11. An (S)-epoxide (VIIIC) according to claim 8which is (S)-1-acetamido-2-acetoxy-3-chloropropane.
 12. A compoundselected from the group consisting of: (1) an (S)-protected alcohol ofthe formula (IVA) X₂—CH₂—C*H(OH)—CH₂—N═CH—X₀  (IVA)  where: (I) X₀ is:(A) A -φ, (B) o-hydroxyphenyl, (C) o-methoxyphenyl, (D) p-methoxyphenyl;(II) X₂ is: (A) —Cl, (B) —Br, (C) p-CH₃-φ-SO₂—, (D) m-NO₂-φ-SO₂—; (2) an(S)-phthalimide alcohol of the formula (IVC)

 where: (A) X₂ is as defined above; (3) an (S)-phthalimide epoxide ofthe formula (IVD)

 where: (A) where # indicates that the atoms marked with a (^(#)) arebonded to each other resulting in the formation of a ring, (4) an(S)-imine of glydidylamine of the formula (IVB)—O^(#)—CH₂—C*^(#)H—CH₂—N═CH—X₀  (IVB) where where X₀ and # are asdefined above.
 13. An (S)-compound according to claim 12 where X₀ is -φor o-hydroxyphenyl and X₂ is —Cl.
 14. An (S)-compound according to claim12 which is (S)-1-benzalimino-3-chloro2-propanol and(S)-1-phthalimido-3-chloro-2-propanol.
 15. An (S)-intermediate of theformula (XV) R_(oxa)—NH—CO—O—C*H[—CH₂—X₂][—CH₂—NH—CO—RN]  (XV) where:(I) R_(oxa) is phenyl substituted with one —F and one substituted aminogroup; (II) R_(N) is C₁-C₅ alkyl; (III) X₂ is: (A) —Cl, (B) —Br, (C)p-CH₃-φ-SO₂—, (D) m-NO₂-φ-SO₂—.
 16. An (S)-intermediate according toclaim 15 where R_(oxa) is:3-fluoro-4-[4-(benzyloxycarbonyl)-1-piperazinyl]phenyl,3-fluoro-4-(4-morpholinyl)phenyl and3-fluoro-4-(4-hydroxyacetylpiperaziny)lphenyl.
 17. An (S)-intermediateaccording to claim 15 where R_(N) is C₁ alky.
 18. An (S)-intermediateaccording to claim 15 where X₂ is —Cl.
 19. An (S)-intermediate accordingto claim 15 where the intermediate is(S)—N-carbo(1′-acetamido-3′-chloro-2′-propoxy)-3-fluoro-4-morpholinylaniline.20. An (S)-oxazolidinone phthalamide intermediate of the formula (XVI)

where: (I) R_(oxa) is phenyl substituted with one —F and one substitutedamino group; (II) X₂ is: (A) —Cl, (B) —Br, (C) p-CH₃-φ-SO₂—, (D)m-NO₂-φ-SO₂—.
 21. An oxazolidinone phthalamide intermediate (XVI)according to claim 21 where R_(oxa) is:3-fluoro-4-[4-(benzyloxycarbonyl)-1-piperazinyl]phenyl,3-fluoro-4-(4-morpholinyl)phenyl and3-fluoro-4-(4-hydroxyacetylpiperaziny)lphenyl.
 22. An oxazolidinonephthalamide intermediate (XVI) according to claim 21 where X₂ is —Cl.23. A process for the preparation of a (S)-3-carbon amino alcohol of theformula (V) X₂—CH₂—C*H(OH)—CH₂—NH₃ ⁺  (V) where X₂ is: (A) —Cl, (B) —Br,(C) p-CH₃-φ-SO₂—, (D) m-NO₂-φ-SO₂— which comprises: (1) contacting anon-nitrogen adduct of formula (I) O═CH—X₀  (I) where X₀ is: (A) -φ, (B)o-hydroxyphenyl, (C) o-methoxyphenyl, (D) p-methoxyphenyl; with aqueousammonia (II) in the presence of an (S)-protected-epoxide of formula(III) X₂—CH₂—C*^(#)H—CH₂—O^(#—)  (III) where: (I) # indicates that theatoms marked with a (#) are bonded to each other resulting in theformation of a ring; (II) X₂ is as defined above, (2) contacting thereaction mixture of step (1) with acid.
 24. A process for thepreparation of an (S)-3-carbon amino alcohol (V) according to claim 23where X₂ is —Cl.
 25. A process for the preparation of a (S)-3-carbonamino alcohol (V) according to claim 23 where the 3-carbon amino alcohol(V) is (S)-1-amino-3-chloro-2-propanol hydrochloride.
 26. A process forthe preparation of an (S)-3-carbon amino alcohol of the formula (V)X₂—CH₂—C*H(OH)—CH₂—NH₃ ⁺  (V) where: (I) X₂ is: (A) —Cl, (B) —Br, (C)p-CH₃-φ-SO₂—, (D) m-NO₂-φ-SO₂— which comprises: (1) contactingphthalimide (VI) with an (S)protected-epoxide of formula (III)X₂—CH₂—C*^(#)H—CH₂—O^(#—)  (III) in the presence of potassiumphthalamide in DMF or DMAC where: (I) # indicates that the atoms markedwith a (^(#)) are bonded to each other resulting in the formation of aring-, (II) X₂ is as defined above; to give an (S)-phthalimide alcoholof formula (IVC)

where X₂ is as defined above and (2) contacting the product of step (1)with aqueous acid.
 27. A process for the preparation of an (S)-3-carbonamino alcohol (V) according to claim 26 where X₂ is —Cl.
 28. A processfor the preparation of an (S)-3-carbon amino alcohol (V) according toclaim 26 where the (S)-3-carbon amino alcohol is(S)-1-amino-3-chloro-2-propanol hydrochloride.
 29. A process for thepreparation of a secondary alcohol of the formula (VMA)X₂—CH₂—C*H(OH)—CH₂—NH—CO—R_(N)  (VIIIA) where: (I) X₂ is: (A) —Cl, (B)—Br, (C) p-CH₃-φ-SO₂—, (D) m-NO₂-φ-SO₂—; (II) R_(N) is C₁-C₅ alkyl;which comprises: (1) contacting an (S)-3-carbon amino alcohol of theformula (V) X₂—CH₂—C*H(OH)—CH₂—NH₃ ⁺  (V) where X₂ is as defined abovewith an acylating agent selected from the group consisting of an acidanhydride of the formula O(CO—R_(N)) where R_(N) is as defined above oran acid halide of the formula R_(N)—CO—X₄ where X₄ is —Cl or —Br andwhere R_(N) is as defined above and a tri(alkyl)amine where alkyl isC₁-C₅.
 30. A process for the preparation of a secondary alcohol of theformula (VIIIA) according to claim 29 where the tri(alkyl)amine istriethylamine.
 31. A process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) of formula (X)R_(oxa)-RING-CH₂—NH—CO—R_(N)  (X) where: (I) R_(N) is C₁-C₅ alkyl; (II)R_(oxa) is phenyl substituted with one —F and one substituted aminogroup; which comprises: (1) contacting a carbamate of formula (IX)R_(oxa)—NH—CO—O—CH₂—X₁  (IX)  where: (I) X₁ is: (A) C₁-C₂₀ alkyl, ` (B)C₃-C₇ cycloalkyl, (C) φ-optionally substituted with one or two: (1)C₁-C₃ alkyl, (2) F—, Cl—, Br—, I—, (D) CH₂═CH—CH₂—, (E) CH₃—CH═CH—CH₂—,(F) (CH₃)₂C═CH—CH₂—, (G) CH₂═CH—, φ-CH═CH—CH₂—, (I) φ-CH₂— optionallysubstituted on φ-with one or two —C₁, C₁-C₄ alkyl, —NO₂, —CN, —CF₃, (J)9-fluorenylmethyl, (K) (Cl)₃C—CH—, (L) 2-trimethylsilylethyl, (M)φ-CH₂—CH₂—, (N) 1-adamantyl, (O) (φ)₂CH—, (P) CH≡C—C(CH₃)_(2—) (O)2-furanylmethyl, (R) isobornyl, (S) —H; (II) R_(oxa) is as definedabove; with an oxygenated amino reagent selected from the groupconsisting of: (1) an (S)-secondary alcohol of the formula (VIIIA)X₂—CH₂—C*H(OH)—CH₂—NH—CO—R_(N)  (VIIIA)  where: (I) X₂ is: (A) —Cl, (B)—Br, (C) p-CH₃-φ-SO₂—, (D) m-NO₂-φ-SO₂—; (II) RN is as defined above; oran (S)-epoxide of the formula (VIIIB)—O^(#)—CH₂—C*^(#)H—CH₂—NH—CO—R_(N)  (VIIIB) where: (I) # indicates thatthe atoms marked with a (#) are bonded to each other resulting in theformation of a ring, (II) RN is as defined above; or an (S)-ester of theformula (VIIIC) X₂—CH₂—C*H(O—CO—R_(N))—CH₂—NH—CO—R_(N)  (VIIIC) where:(I) R_(N) and X₂ are as defined above; in the presence of a lithiumcation and a base whose conjugate acid has a pK_(a) of greater thanabout
 8. 32. A process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N)  (X) according to claim 31 whereR_(oxa) is: 3-fluoro-4-[4-(benzyloxycarbonyl)-1-piperazinyl]phenyA,3-fluoro-4-(4-morpholinyl)phenyl and3-fluoro-4-(4-hydroxyacetylpiperaziny)lphenyl.
 33. A process for theproduction of an (S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) according toclaim 31 where R_(N) is C₁ alkyl.
 34. A process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) according to claim 31 where X₁ is—H.
 35. A process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) according to claim 31 where X₂ is—Cl.
 36. A process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) according to claim 31 where theoxygenated amino reagent is a (S)secondary alcohol (VIIIA) or(S)-epoxide (VIIIB).
 37. A process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) according to claim 31 where the(S)-oxazolidinone-CH₂—NH—CO—RN (X) is(S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide.38. A process for the production of an (S)-oxazolidinone-CH₂—NH—CO—R_(N)of formula (X) R_(oxa)-RING-CH₂—NH—CO—R_(N)  (X) where: (I) R_(N) isC₁-C₅ alkyl; (II) R_(oxa) is phenyl substituted with one —F and onesubstituted amino group which comprises: (1) contacting a carbamate offormula (IX) R_(oxa)—NH—CO—O—CH₂—X₁  (IX) where: (I) X₁ is: (A) C₁-C₂₀alkyl, (B) C₃-C₇ cycloalkyl, (C) φ-optionally substituted with one ortwo: (1) C₁-C₃ alkyl, (2) F—, Cl—, Br—, I—, (D) CH₂=CH—CH₂—, (E)CH₃—CH═CH—CH₂—, (F) (CH₃)₂C═CH—CH₂—, (G) CH₂═CH—, (H)CH═CH—CH₂—, (I)φ-CH₂— optionally substituted on φ-with one or two —Cl, C₁-C₄ alkyl,—NO₂, —CN, —CF₃, (J) 9-fluorenylmethyl, (K) (Cl)₃C—CH₂—, (L)2-trimethylsilylethyl, (M) φ-CH₂—CH₂—, (N) 1-adamantyl, (O) (φ)₂CH—, (P)CH≡C≡C(CH₃)_(2—) (Q) 2-furanylmethyl, (R) isobornyl, (S) —H; (II)R_(oxa) is as defined above; with a phthalimide reagent selected fromthe group consisting of: (1) a phthalimide alcohol of the formula (IVC)

 where: (I) X₂ is: (A) —Cl, (B) —Br, (C) p-CH₃-φ-SO₂—, (D) m-NO₂-φ-SO₂—;(2) a phthalimide epoxide of the formula (IVD)

 where # indicates that the atoms marked with a (^(#)) are bonded toeach other resulting in the formation of a ring to give thering-phthalimide compound of formula (XI)

 where R_(oxa) is as defined above, in the presence of a lithium cationand a base whose conjugate acid has a pK_(a) of greater than about 8,(2) contacting the product of step (1) with aqueous acid, (3) contactingthe reaction mixture of step (2) with an acid anhydride of the formulaO(CO—R_(N))₂ where R_(N) is as defined above or an acid halide of theformula R_(N)—CO—X₄ where X₄ is —Cl or —Br and where R_(N) is as definedabove and a tri(alkyl)amine where alkyl is C₁-C₅.
 39. A process for theproduction of an (S)-oxazolidinone-CH₂—NH—CO—R_(N)(X) according to claim38 where R_(oxa) is:3-fluoro-4-[4-(benzyloxycarbonyl)-1-piperazinyl]phenyl,3-fluoro4-(4-morpholinyl)phenyl and3-fluoro4-(4-hydroxyacetylpiperaziny)lphenyl.
 40. A process for theproduction of an (S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) according toclaim 38 where RN is C₁ alkyl.
 41. A process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) according to claim 38 where X₁ is—H.
 42. A process for the production of an(S)-oxazolidinone-CH₂—NH—CO—R_(N) (X) according to claim 38 where X₂ is—Cl.
 43. A process for the production of an(S)—R_(oxa)-RING-CH₂—NH—CO—R_(N) of the formula (X)R_(oxa)-RING-CH₂—NH—CO—R_(N)  (X) where: (I) RN is C₁-C₅ alkyl; (II)R_(oxa) is phenyl substituted with one —F and one substituted aminogroup which comprises: (1) contacting a carbamate of the formula (IX)R_(oxa)—NH—CO—O—X₁  (IX) where: (I) X₁ is (A) C₁-C₂₀ alkyl, (B) C₃-C₇cycloalkyl, (C) φ-optionally substituted with one or two: (1) C₁-C₃alkyl, (2) F—, Cl—, Br—, I—, (D) CH₂═CH—CH₂—, (E) CH₃—CH═CH—CH₂—, (F)(CH₃)₂C═CH—CH₂—, (G) CH₂═CH—, (H) φ-CH═CH—CH₂—, (I) φ-CH₂— optionallysubstituted on f with one or two —Cl, C₁-C₄ alkyl, —NO₂, —CN, —CF₃, (J)9-fluorenylmethyl, (K) (Cl)₃C—CH₂—, (L) 2-trimethylsilylethyl, (M)φ-CH₂—CH₂—, (N) 1-adamantyl, (O) (+)₂CH—, (P) CH≡C—C(CH₃)_(2—) (O)2-furanylmethyl, (R) isobornyl, (S) —H; (II) R_(oxa) is as definedabove; with a compound selected from the group consisting of a(S)protected alcohol of the formula (IVA)X₂—CH₂—C*^(#)H(OH)—CH₂—N═CH—X₀  (IVA) where: (I) X₀ is: (A) -φ, (B)o-hydroxyphenyl, (C) o-methoxyphenyl, (D) p-methoxyphenyl; (II) X₂ is:(A) —Cl, (B) —Br, (C) p-CH₃-φ-SO₂—, (D) m-NO₂-φ-SO₂—; and a (S)-3-carbonprotected epoxide of the formula (IVB)—O^(#)—CH₂—C*^(#)H—CH₂—N═CH—X₀  (IVB) where: (I) # indicates that theatoms marked with a (^(#)) are bonded to each other resulting in theformation of a ring, (II) X₀ is as defined above in the presence of alithium cation and a base whose conjugate acid has a PK_(a) of greaterthan about 8 to produce a (S)-protected oxazolidinone of the formula(XII) R_(oxa)—RING-CH₂—N═CH—X₀  (XII) where X₀ and R_(oxa) are asdefined above; (2) contacting the reaction mixture of step (1) withaqueous acid to produce an (S)-oxazolidinone free amine of the formula(XIII) and R_(oxa)-RING-CH₂—NH₂  (XIII) (3) contacting the product ofstep (2) with an acylating agent selected from the group consisting ofan acid anhydride of the formula O(CO—R_(N))₂ where R_(N) is as definedabove or an acid halide of the formula R_(N)—CO—X₄ where X₄ is —Cl or—Br and where R_(N) is as defined above and a tri(alkyl)amine wherealkyl is C₁-C₅ where R_(oxa) is as defined above.
 44. A process for theproduction of an (S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) (X) according to claim43 where R_(oxa) is:3-fluoro-4[4-(benzyloxycarbonyl)-1-piperazinyl]phenyl,3-fluoro-4-(4-morpholinyl)phenyl and3-fluoro-(4-hydroxyacetylpiperaziny)lphenyl.
 45. A process for theproduction of an (S)R_(oxa)-RING-CH₂—NH—CO—R_(N) (X) according to claim43 where R_(N) is C₁ alkyl.
 46. A process for the production of an(S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) (X) according to claim 43 where X₀ is-φ or o-hydroxyphenyl.
 47. A process for the production of an(S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) (X) according to claim 43 where X₁ is—H.
 48. A process for the production of an(S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) (X) according to claim 43 where X₂ is—Cl.
 49. A process for the production of an(S)-R_(oxa)-RING-CH₂—NH—CO—R_(N) of the formula (X)R_(oxa)-RING-CH₂—NH—CO—R^(N)  (X) where: (I) R_(N) is C₁-C₅ alkyl; (II)R_(oxa) is phenyl substituted with one —F and one substituted aminogroup which comprises: (1) contacting a carbamate of the formula (IX)R_(oxa)—NH—CO—O—CH₂—X₁  (IX) where: (I) X₁ is: (A) C₁-C₂₀ alkyl, (B)C₃-C₇ cycloalkyl, (C) φ-optionally substituted with one or two: (1)C₁-C₃ alkyl, (2) F—, Cl—, Br—, I—, (D) CH₂═CH—CH₂—, (E) CH₃—CH═CH—CH₂—,(F) (CH₃)₂C═CH—CH₂—, (G) CH₂=CH—, (H) O—CH═CH—CH₂—, (I) φ-CH₂—optionally substituted on φ-with one or two —C₁, C₁-C₄ alkyl, —NO₂, —CN,—CF₃, (J) 9-fluorenylmethyl, (K) (Cl)₃C—CH₂—, (L) 2-trimethylsilylethyl,(M) φ-CH₂—CH₂—, (N) 1-adamantyl, (O) (φ)₂CH—, (P) CH≡C—C(CH₃)_(2—) (Q)2-furanylmethyl, (R) isobornyl, (S) —H; (II) R_(oxa) is as definedabove; with an (S)-3-carbon amino alcohol (V) where X₂ is as definedabove in the presence of a lithium cation and a base whose conjugateacid has a pK_(a) of greater than about 8 to produce an(S)-oxazolidinone free amine of the formula (XIII)R_(oxa)—RING-CH₂—NH₂  (XIII)  where R_(oxa) is as defined above, and (2)acylating the (S)-oxazolidinone free amine (XIII) with an acylatingagent selected from the group consisting of an acid anhydride of theformula O(CO—R_(N))₂ where R_(N) is as defined above or an acid halideof the formula R_(N)—CO—X₄ where X₄ is —Cl or —Br and where R_(N) is asdefined above and a tri(alkyl)amine where alkyl is C₁-C₅.
 50. A processfor the production of an (S)—R_(oxa)—RING-CH₂—NH—CO—R_(N) (X) accordingto claim 49 where R_(oxa) is:3-fluoro-4-[4-(benzyloxycarbonyl)-1-piperazinyl]phenyl,3-fluoro-4-(4-morpholinyl)phenyl and3-fluoro-4-(4-hydroxyacetylpiperaziny)lphenyl.
 51. A process for theproduction of an (S)—R_(oxa)—RING-CH₂—NH—CO—R_(N) (X) according to claim49 where R_(N) is C₁ alkyl.
 52. A process for the production of an(S)—R_(oxa)—RING—CH₂—NH—CO—R_(N) (X) according to claim 49 where X₁ is—H.
 53. A process for the production of an(S)—R_(oxa)—RING-CH₂—NH—CO—R_(N) (X) according to claim 49 where X₂ is—Cl.